Androgen deficiency may contribute to anemia, loss of muscle and bone strength and depression in men with chronic kidney disease (CKD). Preliminary studies indicate that drugs that block the renin angiotensin system (RAS) reduce circulating levels of testosterone in men with CKD. Therefore, men with CKD taking RAS blockers are at high risk for complications of androgen deficiency. The overall objective of this application is to investigate the importance and clarify the mechanism of testosterone suppression associated with RAS blockers in men with CKD. A secondary objective is to identify appropriate directions for future studies aimed at correcting testosterone deficiency due to RAS blockers. The research team includes practicing academic nephrologists (PI and Co-PI), basic researchers (Co-PI and Research Associate) and experienced research staff to perform these clinical studies. The first specific aim is to evaluate the role of the RAS in regulation of testosterone in men with CKD. This will be done by observing the effects angiotensin converting enzyme inhibitors and angiotensin II receptor blockers on hCG-stimulated testosterone production. RAS blockade also lowers erythropoietin (EPO) levels, and both testosterone and EPO deficiency can cause anemia. The evidence from the literature indicating interactions between EPO and testosterone in other settings suggests a potentially important counter-regulation of EPO and testosterone. Therefore, experiments are proposed to study the interaction between testosterone and EPO in men with CKD taking RAS blockers by selectively replacing EPO and observing the effect on testosterone, and then replacing testosterone and observing the effect on EPO. The results of this work could have important therapeutic implications since EPO replacement in men with CKD on RAS blockers may reverse anemia but leave the other adverse effects of androgen deficiency unaddressed. On the other hand, if testosterone replacement is effective in treating anemia in this setting, then this approach in men with CKD on RAS blockers may be more effective than EPO in terms of restoring all of the aspects of health jeopardized by testosterone deficiency. Drugs that block the RAS are widely used because of their proven value in preventing progression of kidney failure as well as many of the associated cardiovascular complications. However, the impact of these important drugs on androgens in men with CKD has not been well studied and needs clarification.